chr9-134699909-C-T

Variant names:

• chr9-134699909-C-T
• rs41306397
• NM_000093.5:c.278C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.278C>T​(p.Ala93Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,613,882 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A93G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: COL5A1 NM_000093.5 missense, splice_region
• Scores: Splicing: ADA: 0.02236
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.31
• Publications: 13 publications found

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

COL5A1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009988606).
• BP6: Variant 9-134699909-C-T is Benign according to our data. Variant chr9-134699909-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (304/152348) while in subpopulation NFE AF = 0.00354 (241/68030). AF 95% confidence interval is 0.00318. There are 0 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 304 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000093.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.278C>T	p.Ala93Val	missense splice_region	Exon 3 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.278C>T	p.Ala93Val	missense splice_region	Exon 3 of 66	NP_001265003.1	P20908-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.278C>T	p.Ala93Val	missense splice_region	Exon 3 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.278C>T	p.Ala93Val	missense splice_region	Exon 3 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.278C>T	p.Ala93Val	missense splice_region	Exon 3 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00194 AC: 487 AN: 250912 AF XY: 0.00204

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00327 AC: 4781 AN: 1461534 Hom.: 8 Cov.: 32 AF XY: 0.00330 AC XY: 2401 AN XY: 727040

African (AFR) AF: 0.000358 AC: 12 AN: 33478

American (AMR) AF: 0.000827 AC: 37 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000905 AC: 78 AN: 86220

European-Finnish (FIN) AF: 0.00169 AC: 90 AN: 53216

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00392 AC: 4361 AN: 1111904

Other (OTH) AF: 0.00326 AC: 197 AN: 60392

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00199 AC XY: 148 AN XY: 74508

African (AFR) AF: 0.000553 AC: 23 AN: 41582

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00354 AC: 241 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00299 Hom.: 0

Bravo AF: 0.00179

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00190 AC: 231

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)
-	-	1	Marfan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.046
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.048	D
Polyphen		0.0060	B
Vest4		0.13
MVP		0.16
MPC		0.21
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.039
gMVP		0.20
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.022
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41306397; hg19: chr9-137591755; COSMIC: COSV105286585;